Technology appraisal guidance Published: 23 November 2016

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Nivolumab for previously treated advanced renal cell carcinoma Technology appraisal guidance Published: 23 November 2016 NICE All rights reserved. Subject to Notice of
Nivolumab for previously treated advanced renal cell carcinoma Technology appraisal guidance Published: 23 November 2016 NICE All rights reserved. Subject to Notice of rights ( Your responsibility The recommendations in this guidance represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, health professionals are expected to take this guidance fully into account, alongside the individual needs, preferences and values of their patients. The application of the recommendations in this guidance are at the discretion of health professionals and their individual patients and do not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian. Commissioners and/or providers have a responsibility to provide the funding required to enable the guidance to be applied when individual health professionals and their patients wish to use it, in accordance with the NHS Constitution. They should do so in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible. Page 2 of Contents 1 Recommendations The technology Evidence Committee discussion... 7 Treatment pathway... 7 Comparators... 8 Clinical effectiveness... 8 Cost effectiveness Innovation End-of-life considerations Pharmaceutical Price Regulation Scheme (PPRS) Conclusion Summary of appraisal committee's key conclusions Implementation Appraisal committee members and NICE project team Appraisal committee members NICE project team Update information... Page 3 of 1 Recommendations 1.1 Nivolumab is recommended, within its marketing authorisation, as an option for previously treated advanced renal cell carcinoma in adults, when the company provides nivolumab in line with the commercial access agreement with NHS England. Page 4 of 2 The technology Description of the technology Marketing authorisation Nivolumab (Opdivo, Bristol Myers Squibb) is a human monoclonal antibody that blocks an immune checkpoint protein receptor called programmed cell death protein 1 (PD-1) to promote an anti-tumour response. Nivolumab 'as monotherapy is indicated for the treatment of advanced renal cell carcinoma after prior therapy in adults'. Before the marketing authorisation was granted (April 2016), nivolumab was available in the NHS through the early access to medicines scheme. Adverse reactions Recommended dose and schedule Price The most common adverse reactions with nivolumab in clinical trials were tiredness, rash, pruritus, diarrhoea, nausea and decreased appetite (occurring in more than 10% of people). For full details of adverse reactions and contraindications, see the summary of product characteristics. 3 mg/kg given intravenously every 2 weeks. The list price is 439 per 40-mg vial or 1,097 per 100-mg vial. The pricing arrangement considered during guidance development was that Bristol-Myers Squibb had agreed a patient access scheme with the Department of Health. This scheme provided a simple discount to the list price of nivolumab with the discount applied at the point of purchase or invoice. After guidance publication in November 2016, the company agreed a commercial access agreement with NHS England that replaces the patient access scheme on equivalent terms. The financial terms of the agreement are commercial in confidence. Page 5 of 3 Evidence The appraisal committee (section 6) considered evidence submitted by Bristol Myers Squibb and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence. Page 6 of 4 Committee discussion The appraisal committee reviewed the data available on the clinical and cost effectiveness of nivolumab, having considered evidence on the nature of renal cell carcinoma and the value placed on the benefits of nivolumab by people with the condition, those who represent them, and clinical experts. It also took into account the effective use of NHS resources. 4.1 The committee considered the experience of people with advanced renal cell carcinoma. It heard from the clinical and patient experts that nivolumab could extend life and improve its quality. It heard that nivolumab was generally well tolerated, and usually caused fewer side effects than other treatments such as axitinib and everolimus. The committee noted that one of the patient experts who had had nivolumab was able to continue working. The committee recognised nivolumab is an intravenous drug whereas axitinib and everolimus are oral. The committee heard that people prefer oral treatments that they can have at home, but are willing to travel to have intravenous infusions to get more effective therapy. The committee was aware of several comments received during consultation from patients and carers who emphasised the importance of having access to nivolumab. Treatment pathway 4.2 The committee heard from the clinical experts that most people in the NHS with newly diagnosed advanced renal cell carcinoma would be offered one of two tyrosine kinase inhibitors; either pazopanib or sunitinib, as recommended in NICE's technology appraisal guidance. If the disease progresses and they are fit enough to have further treatment, most people are then offered a different tyrosine kinase inhibitor, axitinib, as recommended in NICE's technology appraisal guidance. The committee understood that everolimus (a mammalian target of rapamycin [mtor] inhibitor) is currently available through the Cancer Drugs Fund for people who have had treatment with only 1 tyrosine kinase inhibitor and for whom axitinib is contraindicated or not tolerated. It heard from the clinical experts that, if given a choice of axitinib or everolimus for previously treated renal cell carcinoma, they would prefer axitinib because they expect a better response to a second tyrosine kinase inhibitor than an mtor inhibitor. The committee heard that, in current practice, everolimus is offered to people who have previously had tyrosine kinase inhibitor-related adverse events such as hypertension, or who cannot tolerate axitinib, or for whom axitinib is Page 7 of contraindicated. The committee heard that after 2 treatments, no further treatments are available in the NHS and people are offered best supportive care. Comparators 4.3 The committee heard from the clinical experts that they would like to offer nivolumab to people who have had 1 or 2 previous treatments. The experts also advised that a small number of people cannot tolerate axitinib or everolimus, but may be able to have nivolumab because of its favourable toxicity profile. For people who have had 1 previous treatment, the committee agreed that the relevant comparator for nivolumab is: axitinib, for most people everolimus, for people who cannot have axitinib best supportive care, for people who cannot have axitinib or everolimus. The committee further concluded that, for people who have had 2 previous treatments, best supportive care is the appropriate comparator for nivolumab. Clinical effectiveness Survival benefit of nivolumab compared with everolimuserolimus 4.4 The committee noted that the evidence for nivolumab mostly came from CheckMate 025, a well-conducted open-label randomised controlled trial with 821 patients that compared nivolumab with everolimus. Overall survival was the primary outcome. The committee noted that, in CheckMate 025, patients randomised to nivolumab lived longer (median 25.0 months) than patients randomised to everolimus (median 19.6 months; 95% confidence interval [CI] 17.6 to 23.1), resulting in a hazard ratio of 0.73 (98.5% CI 0.57 to 0.93; p=0.002). The committee noted that the CheckMate 025 trial showed no difference in progression-free survival between nivolumab and everolimus. The committee concluded that, compared with everolimus, nivolumab extended overall survival, but not progression-free survival. Page 8 of 4.5 The committee considered the extent to which nivolumab extends survival when compared with everolimus: The committee considered the survival data from CheckMate 025 to be immature because, at the time of the interim analysis that led to the study stopping (July 2015), 398 out of 821 (48%) patients had died and median follow-up was only about 18 months. The company's submission stated that, when nivolumab is used to treat melanoma, survival curves show 'long tails' for overall survival meaning that some patients survive for a long time. The clinical experts advised that it was plausible that an overall survival curve with a 'long tail' would also be shown for renal cell carcinoma treated with nivolumab. The committee noted that this opinion was reiterated in the company's consultation response, which contained advice from 2 consultant oncologists. The committee concluded that the most robust results came from the larger CheckMate 025 trial, which showed that nivolumab extended life by a median of 5.4 months compared with everolimus, but also concluded that there was uncertainty about the extent of the survival benefit when measured over the long term. Generalisability of the CheckMate 025 population 4.6 The committee heard from the clinical experts that the characteristics of the patients in CheckMate 025 were similar to those of the people in their NHS clinics. The committee concluded the trial results were generalisable to the NHS. Subgroups with 1 or 2 previous treatments 4.7 The committee recognised that the trial included a mix of people who had had 1 previous treatment with a tyrosine kinase inhibitor (72% of patients) and people who had had 2 previous tyrosine kinase inhibitors (28%). During consultation the company clarified that a subgroup analysis based on number of previous treatments showed that the treatment effect of nivolumab compared with everolimus was clinically and statistically significant both for patients who had 1 previous tyrosine kinase inhibitor (hazard ratio 0.79; 95% CI 0.63 to 0.99) and patients who had 2 previous tyrosine kinase inhibitors (hazard ratio 0.65; 95% CI 0.43 to 0.99). The committee concluded that nivolumab prolonged Page 9 of overall survival compared with everolimus both for people who had had 1 previous treatment and people who had had 2 previous treatments. Subsequent treatments in CheckMate The committee was aware that people generally continue having nivolumab until disease progression, or some time beyond it, after which some people then try other therapies. The committee heard from the company that the trial protocol prohibited patients from switching treatments during the trial (that is, patients randomised to everolimus could not have nivolumab after progression), yet patients in both the nivolumab and everolimus groups had subsequent treatments including everolimus and tyrosine kinase inhibitors. The committee heard from the clinical experts that these subsequent treatments extend survival, but that they are not given in NHS practice after people have had 2 treatments. The committee recognised the use of these treatments was unlikely to have been equal between both groups in CheckMate 025, which may have confounded the results, although the direction of the bias was not clear. The committee concluded that this should be taken into account in any analyses. Duration of nivolumab treatment 4.9 The committee noted that the summary of product characteristics allows for nivolumab treatment to continue after disease progression, as did the trial. It heard from the clinical experts that about 10% of people have nivolumab for a short time after disease progression. The committee concluded that treatment after disease progression was likely to reflect NHS practice, and that the company had appropriately included this in its economic model. Network meta-analysis 4.10 The committee understood that, because there were no head-to-head trials comparing nivolumab with axitinib or best supportive care, the company had done a network meta-analysis to compare the treatments indirectly. To compare nivolumab with best supportive care, the network linked CheckMate 025 (nivolumab compared with everolimus) with the RECORD-1 trial (everolimus compared with best supportive care) using everolimus as a common comparator. To compare nivolumab with axitinib, the network joined these 2 trials to 2 other trials (TARGET, sorafenib compared with best supportive care; AXIS, axitinib compared with sorafenib). It noted advice from the evidence review group Page 10 of (ERG) that the results were likely to be biased because of differences between trials: Number of previous treatments: CheckMate 025 and RECORD-1 recruited patients who had had 1 or 2 previous tyrosine kinase inhibitors, while AXIS and TARGET recruited patients who had only had 1 previous treatment with a tyrosine kinase inhibitor. Choice of previous treatments: The committee heard from the clinical experts that previous therapy affects response to subsequent treatments. The committee acknowledged that the company had partly addressed this by only using data from the subgroup of patients in the AXIS trial who previously had sunitinib. But the trials still differed in the choice of previous treatments. Prognosis of patients at baseline: The committee noted that patients in AXIS had a poorer prognosis than those in CheckMate 025, measured using the Memorial Sloan Kettering Cancer Center (MSKCC) tool for predicting renal cancer prognosis. The committee heard from the company that both trials used the MSKCC tool, but that 1 component (performance status) was measured using different tools in each trial. The company stated that this explained the difference in prognosis and that the trial populations were similar. The committee concluded that there was no way to assess whether the prognosis of the trial patients was similar. Subsequent treatments: The ERG noted that Motzer et al. (2013) raised concerns that the results of the AXIS trial may have been confounded by differences between treatment groups with respect to subsequent treatments. The committee was concerned that the company had not explored whether an imbalance in the choice of subsequent treatments, which extended life and were not routinely available in the NHS, could have biased the AXIS results and hence the company's network metaanalysis The committee assessed the effect of the limitations in the network metaanalysis. It heard from the ERG that in its opinion the poorer prognosis of patients in AXIS, and the impact of subsequent treatments in that trial, meant that the results were likely to have underestimated the effectiveness of axitinib, and so overestimated the relative effectiveness of nivolumab with respect to overall survival. The committee concluded that the company's network metaanalysis could potentially have been biased in favour of nivolumab. Page 11 of Effectiveness eness of axitinib compared with everolimus erolimus (and, by extension, nivolumab) 4.12 The committee was aware that to be able to estimate the relative effectiveness of nivolumab compared with axitinib, the company's original model used the results of CheckMate 025 (nivolumab compared with everolimus) but adjusted the everolimus arm, using the network meta-analysis results to represent the effectiveness of axitinib. Two key inputs to the economic model were therefore the hazard ratios for progression-free survival and overall survival comparing axitinib with everolimus. The committee noted that the company's network meta-analysis showed axitinib was less effective than everolimus (the results are academic-in-confidence and cannot be reported here). The committee questioned the face-validity of this result. It heard from clinical experts that in their experience, axitinib and everolimus have similar treatment effects. The committee also heard that clinicians would usually choose axitinib over everolimus (unless a person could not tolerate tyrosine kinase inhibitors) because they expected a better response with a second tyrosine kinase inhibitor than with an mtor inhibitor. The committee noted that a published indirect treatment comparison of axitinib and everolimus showed no difference in progression-free survival (Sherman et al. 2015). Cost effectiveness The committee acknowledged the limited evidence, but concluded that axitinib and everolimus were likely to have similar effectiveness and that it was appropriate to use a hazard ratio of 1 for overall survival and progression-free survival in the model. Both the company and ERG used hazard ratios of 1 in their revised base-case analyses submitted after consultation The committee agreed that the structure of the 6-stage, partitioned-survival economic model was appropriate. It noted that the model represented patients who had had either 1 or 2 previous tyrosine kinase inhibitors. The committee would have preferred to consider separate analyses for patients who had 1 previous tyrosine kinase inhibitor and patients who had 2 previous tyrosine kinase inhibitors because the comparators that reflect NHS practice differ for each group (see section 4.3) and the patients in the groups likely differ in ways that might affect treatment effectiveness. However, neither the company nor Page 12 of the ERG presented subgroup analyses. The committee accepted that the analyses for the overall population (representing patients who had had either 1 or 2 previous tyrosine kinase inhibitors) were suitable for decision-making. Modelling overall survival 4.14 Because the trial data were immature (see section 4.5), the committee was concerned that a large proportion of the benefit attributed to nivolumab for extending life was based on extrapolation rather than on trial data. The committee was aware that, for predicting overall survival with nivolumab and everolimus, the company fitted a generalised gamma model to extrapolate the data from CheckMate 025. The committee noted that this model relies on the 'accelerated failure-time' assumption, but this assumption had not been formally tested by the company. In the committee's opinion, the survival curves converged suggesting that the assumption was not met. The committee noted that an alternative approach was to use independent models for each treatment group (that is, separate models for nivolumab and everolimus), as presented by the ERG in a scenario analysis requested by the committee for the second committee meeting. The committee noted that the independent log-logistic model predicted that 19% of patients treated with everolimus would be alive after 5 years, whereas the company's clinical experts predicted this would be only 10% to 12% in practice. The committee concluded that the independent log-logistic model overpredicted survival with everolimus. The committee preferred to base its decision on a single generalised gamma model to predict survival with both nivolumab and everolimus, as had been done in the company and ERG's base cases The committee discussed the company's scenario analysis, provided after consultation, using a 'model averaging' approach. The company gave 50% weight to the base-case model and 50% weight to a model assuming a greater long-term survival benefit for nivolumab (see section 4.5). For the latter model, based on data from CheckMate 003 and advice from 2 oncologists, the company assumed that patients whose disease was treated with nivolumab who survive for 5 years would have the same risk of death after 5 years as the age-matched general population. This scenario ana
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